Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a progressive, fatal, neurodegenerative disease that affects nerve cells in the brain and the spinal cord . Currently, there is no cure for ALS and no effective treatment to halt, or reverse, the progression of the disease.

The pathogenesis of numerous human multifaceted devastating diseases, including a
variety of neurodegenerative and autoimmune diseases, is associated with alterations in the gut
microbiota; however, the underlying mechanisms are not completely understood. Our recent human metagenome and phagobiota proteome analyses and studies in relevant animal models suggested that bacterial viruses might be implicated in the progression and maintenance of at least some pathologies, including those associated with protein misfolding. Here, for the first time, we propose the concept of bacteriophages as human pathogens. We suggest that bacterial viruses have different
ways to directly and indirectly interact with eukaryotic cells and proteins, leading to human diseases. Furthermore, we suggest different causes of bacteriophages infection on the basis of the unique ways of interplay of phages, microbiota, and the human host. This concept opens a discussion of the role of bacteriophages as previously overlooked pathogenic factors and suggests that bacterial viruses have to be further explored as a diagnostic and treatment target for therapeutic intervention.

Prions are proteins that can self-propagate, leading to the misfolding of proteins. In addition to the previously demonstrated pathogenic roles of prions during the development of different mammalian diseases, including neurodegenerative diseases, they have recently been shown to represent an important functional component in many prokaryotic and eukaryotic organisms and bacteriophages, confirming the previously unexplored important regulatory and functional roles. However, an in-depth analysis of these domains in eukaryotic viruses has not been performed. Here, we examined the presence of prion-like proteins in eukaryotic viruses that play a primary role in different ecosystems and that are associated with emerging diseases in humans. We identified relevant functional associations in different viral processes and regularities in their presence at different taxonomic levels. Using the prion-like amino-acid composition computational algorithm, we detected 2679 unique putative prion-like domains within 2,742,160 publicly available viral protein sequences. Our findings indicate that viral prion-like proteins can be found in different viruses of insects, plants, mammals, and humans. The analysis performed here demonstrated common patterns in the distribution of prion-like domains across viral orders and families, and revealed probable functional associations with different steps of viral replication and interaction with host cells. These data allow the identification of the viral prion-like proteins as potential novel regulators of viral infections.

IPrions are molecules characterized by self-propagation, which can undergo a conformational switch leading to the creation of new prions. Prion proteins have originally been associated with the development of mammalian pathologies; however, recently they have been shown to contribute to the environmental adaptation in a variety of prokaryotic and eukaryotic organisms. Bacteriophages are widespread and represent the important regulators of microbiota homeostasis and have been shown to be diverse across various bacterial families. Here, we examined whether bacteriophages contain prion-like proteins and whether these prion-like protein domains are involved in the regulation of homeostasis. We used a computational algorithm, prion-like amino acid composition, to detect prion-like domains in 370,617 publicly available bacteriophage protein sequences, which resulted in the identification of 5040 putative prions. We analyzed a set of these prion-like proteins, and observed regularities in their distribution across different phage families, associated with their interactions with the bacterial host cells. We found that prion-like domains could be found across all phages of various groups of bacteria and archaea. The results obtained in this study indicate that bacteriophage prion-like proteins are predominantly involved in the interactions between bacteriophages and bacterial cell, such as those associated with the attachment and penetration of bacteriophage in the cell, and the release of the phage progeny. These data allow the identification of phage prion-like proteins as novel regulators of the interactions between bacteriophages and bacterial cells.

Bacteriophage infections of microbiota can lead to leaky gut in an experimental rodent model. Gutpathogens (2017) 8:33.

Scientific Reports (2017)

Bacteriophages as potential new mammalian pathogens

Publication Type

Jornal article

Authors

George V. TetzKelly V. Ruggles

Hua Zhou

Adriana Heguy

Aristotelis Tsirigos

Victor Tetz

Abstract

Increased intestinal permeability and translocation of gut bacteria trigger various polyaetiological diseases associated with chronic inflammation and underlie a variety of poorly treatable pathologies. Previous studies have established a primary role of the microbiota composition and intestinal permeability in such pathologies. Using a rat model, we examined the effects of exposure to a bacteriophage cocktail on intestinal permeability and relative abundance of taxonomic units in the gut bacterial community. There was an increase in markers of impaired gut permeability, such as the lactulose/mannitol ratio, plasma endotoxin concentrations, and serum levels of inflammation-related cytokines, following the bacteriophage challenge. We observed significant differences in the alpha diversity of faecal bacterial species and found that richness and diversity index values increased following the bacteriophage challenge. There was a reduction in the abundance of Blautia, Catenibacterium, Lactobacillus, and Faecalibacterium species and an increase in Butyrivibrio,Oscillospira and Ruminococcus after bacteriophage administration. These findings provide novel insights into the role of bacteriophages as potentially pathogenic for mammals and their possible implication in the development of diseases associated with increased intestinal permeability.

Infection of Microbiota by Bacteriophages Can Be Considered a New Group of Viral Diseases of Mammals Including Humans. ASM Microbe (2017)

ASM Microbe (2017)

Infection of Microbiota by Bacteriophages Can Be Considered a New Group of Viral Diseases of Mammals Including Humans

Publication Type

Oral presentation

Authors

George TetzVictor Tetz

Abstract

Background: The objective of this study was to assess the effect of microbiota treatment with bacteriophages on the intestinal permeability in vivo and to evaluate the possibility that the infection of microbiota by bacteriophages may affect mammals.Methods: We studied alterations in the host macroorganism and increased intestinal permeability as a result of a direct effect of bacteriophage cocktail. Healthy adult, albino Wistar rats, weighing 180-220g were given daily (for 10 days) phage cocktail (1.5 ml of 1×106 plaque forming units/ml) active against Enterobacteriaceae, Staphylococcaceae, Streptococcaceae, and Pseudomonadaceae families (1). The lactulose-mannitol ratio was used as a marker of intestinal permeability (2). Circulating immune complexes (CIC) were evaluated as markers of endogenous intoxication (3). Metagenomic analysis was used to characterize the composition of microbiota before and after phage challenge.Results: After 10 days of challenge, the rats showed weight loss, decreased activity. They displayed a significantly elevated lactulose:mannitol ratio with the mean increase 2.4 fold (2). The level of CIC was more than 2.5 times higher as compared to before treatment, indicating endogenous intoxication, caused by leaky gut (3). Metagenomic analysis revealed phage-induced altered microbiota composition that led to the increased intestinal permeability and transcriptome alterations were relevant to leaky gut syndrome.

Conclusions: To our knowledge, this study for the first time indicates the link between bacteriophages and mammalian pathologies associated with increased intestinal permeability such as systemic inflammatory and psychological or autoimmune disorders. This study demonstrates that increased intestinal permeability may be induced by bacteriophages that affect microbiota. We propose that infection of microbiota by bacteriophages can be considered a new group of viral diseases of mammals including humans (4).

Bacteriophage infections of microbiota can lead to leaky gut in an experimental rodent model. Gutpathogens (2016) 2016; 8:33

Gut pathogens (2016)

Bacteriophage infections of microbiota can lead to leaky gut in an experimental rodent model

Publication Type

Journal Article

Authors

George TetzVictor Tetz

Abstract

Increased intestinal permeability and translocation of gut microbiota from the intestinal lumen to the systemic circulation predispose patients to various diseases and may be one of the main triggers thereof. The role of microbiota in increased intestinal permeability is under intensive investigation. Here, we studied alterations in the host and increased intestinal permeability as a direct effect of treatment with a bacteriophage cocktail. After 10 days of challenge, the rats showed weight loss, messy hair, and decreased activity. Additionally, they displayed a significantly elevated lactulose:mannitol ratio and the level of circulating immune complexes. To our knowledge, this study demonstrates for the first time that increased intestinal permeability may be induced by bacteriophages that affect the microbiota.